DEVELOPMENT OF THE SECOND GENERATION OF GENERAL AMBER FORCE FIELD

第二代通用琥珀力场的研制

• 批准号: 8171771
• 负责人: JUNMEI WANG
• 金额: $ 0.14万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171771
• 关键词: Amber; Biological; Charge; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Computer software; Computers; Development; Drug Design; Elements; Equilibrium; Frequencies; Funding; Generations; Goals; Grant; Institution; Length; Maps; Metals; Modeling; Molecular Structure; Nucleic Acids; Paper; Procedures; Proteins; Public Domains; Publishing; Research; Research Personnel; Resources; Scanning; Scheme; Source; Stretching; Structure; System; United States National Institutes of Health; Work; base; database structure; improved; molecular mechanics; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Molecular mechanics (MM) are the key component in the armamentarium used by computational chemists and biologists to study molecular structures and energies for both organic and biological molecules. Force field that describes the energy of a system with bond stretching, bond angle bending and torsional angle twisting etc, is the cornerstone of a MM model. Most the widely used force fields, including AMBER, CHARMM, MMFF, MM3, are developed to study a specific class of molecules, either biological or organic molecules. The purpose of this project is to develop a general force field that works well for both biological and organic molecules. A universal, self consistent and well parameterized force field is essential to perform structure-based drug design. The AMBER force fields (parm94, parm99, parm99SB, parm02) was originally developed for protein and nucleic acids. The fact that AMBER has only limited parameters for organic molecules has prevented it from being widely used in drug design. Recently, we put some effort to extend AMBER to cover the chemical space of organic molecules that are made up of H, C, N, O, S, P, F, Cl, Br, I. A paper on this general AMBER force field has been published (J. Comput. Chem., 25, 1157-1174, 2004). To further improve GAFF and extend this general force field to cover more chemical spaces that include metallic elements, we plan to (1) perform ab initio optimizations for up to 40,000 organic molecules to derive bond length and bond angle equilibrium parameters; (2) carry out ab initio torsional angle scanning to derive the force constants for the missing torsional parameters; (3) do frequency analysis for up to 5000 organic molecules to further improve the force constants of bond stretching, bond angle bending as well as torsional angle twisting; (4) investigate different function forms of modeling metallic bond angles that typically have more than one equilibrium bond angles (such as 90 and 180 degrees in octahedral configuration), do Steps (1) to (3) for metallic model compounds selected from CSD (Crystal Structure Database) and the truncated protein-metal, DNA-metal systems; (5) develop a polarizable version of GAFF to be used in combination with polarizable protein/nucleic acid force fields; (6) develop an efficient charge model that mimic the HF/6-31G(d) ESP charges using the Gasteigers scheme. With those improvements, we are confident that the second version of GAFF will be a significantly better universal force field for drug design. Many of the planned calculations have been done; however, we need more computer resource to achieve the goals. According to our Amber force fields development road map,the second generation GAFF and the first version of polarizable GAFF will be released in Year 2009. We also plan to develop a software package (an improved version of parmscan) to facilitate the procedure of force field parameterization and this package will be put in public domain for free download.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 分子力学（MM）是计算化学家和生物学家使用的有机和生物分子分子结构和能量的武术中的关键组成部分。用键拉伸，键角弯曲和扭转角扭曲等描述系统能量的力场是MM模型的基石。开发了大多数广泛使用的力场，包括琥珀，CHARMM，MMFF，MM3，用于研究特定的分子，无论是生物学或有机分子。该项目的目的是开发一个对生物学和有机分子都很好的一般力场。通用，自我一致且参数良好的力场对于执行基于结构的药物设计至关重要。琥珀色力场（PARM94，PARM99，PARM99SB，PARM02）最初是针对蛋白质和核酸开发的。琥珀只有有限的有机分子参数，这一事实阻止了它在药物设计中被广泛使用。最近，我们付出了一些努力来扩展琥珀色，以涵盖由H，C，C，N，O，S，P，F，Cl，BR，BR组成的有机分子的化学空间，该论文已经发表了一篇有关琥珀色力场的论文（J.Comput。Chem。，25，1157-1157-1174，2004，2004）。为了进一步改善吞咽状态并扩展了该一般力场以覆盖包括金属元素在内的更多化学空间，我们计划（1）对多达40,000个有机分子进行初始优化，以得出键长和键角平衡参数； （2）进行从头开始扭转角度扫描，以得出缺失的扭转参数的力常数； （3）对多达5000个有机分子进行频率分析，以进一步改善键拉伸，键角弯曲以及扭转角扭曲的力常数； （4）研究建模金属键角的不同功能形式，通常具有一个以上的平衡键角（例如八面体构型中的90和180度），对于从CSD（晶体结构数据库）和截断的蛋白质蛋白质 - 蛋白质计量，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL，DNA-METAL SYSTERS中选择的步骤（1）至（3） （5）开发可与可极化的蛋白/核酸力场结合使用的可极化版本的GAFF； （6）开发一个有效的电荷模型，该模型使用Gasteigers方案模仿HF/6-31G（D）ESP电荷。通过这些改进，我们相信第二版GAFF将成为药物设计的更好的通用力领域。许多计划的计算已经完成；但是，我们需要更多的计算机资源来实现目标。根据我们的Amber Force Fields开发路线图，第二代GAFF和第一个可极化GAFF的版本将于2009年发布。我们还计划开发一个软件包（改进的Parmscan版本），以促进力场参数化的过程，该软件包将在公共领域中放置。